This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This program project is a collaborative study with Dr. Lieberman (Harvard) to develop an effective microbicide based on small interfering RNA (siRNA) technology. These studies were initiated when Dr. Lieberman first showed that siRNA targeted against herpes virus could completely prevent vaginal transmission of herpes to mice. We thus hypothesized that targeting siRNA against an HIV receptor such as CD4 or CCR5 could also prevent vaginal transmission of HIV. However, in tests in macaques over the last 2 years, we have not been able to silence CCR5 expression in deeper parts of the vagina where CCR5 exists. As expected, the siRNA molecules penetrate the vaginal epithelium, but we have not been able to silence CCR5 on lymphocytes in the deep vaginal mucosal which is where we now believe HIV establishes infection (dendritic cells carry it in a nonspecific manner to the underlying tissues). Since we cannot thus far significantly reduce CCR5 levels in deep tissues with this technology, we have postponed any SIV challenge studies and instead we are going to switch our approach and try two new approaches. The first approach will be to silence lymphocyte activation using siRNA and if this fails, we will switch to preventing herpesvirus transmission. Since genital herpes is associated with markedly increased rates of HIV transmission, and since genital herpes infects over 20% of adolescents/adults, this approach is also in line with our goals to reduce HIV transmission. In a recent meeting with our NIH program officials, we were approved to switch this program from one to prevent vaginal HIV transmission to one that targets genital herpes transmisson.